1. Field of the Invention
The present invention relates generally to the antimicrobial preservation of aqueous pharmaceutical compositions. In particular, the present invention relates to the antimicrobial preservation of pharmaceutical compositions containing cyclodextrins.
2. Description of Related Art
Cyclodextrins are known to possess a number of uses in pharmaceutical formulations. For example, cyclodextrins are known to increase the solubility of insoluble or poorly soluble drug compounds, to increase the stability of chemically labile drugs in pharmaceutical formulations, and to increase the comfort or mask the taste of active drugs. See, U.S. Pat. No. 4,727,064 (Pitha) and EP 0 149 197 B1 (Janssen Pharmaceutica N.V.).
There have been a number of attempts to derivative cyclodextrins in order to decrease toxicity or increase solubility. For example, hydroxy-propyl-beta-cyclodextrin is a derivative which has been shown to have a relatively low toxicity and a high aqueous solubility as compared to the parent compound, beta-cyclodextrin. In addition to hydroxy-propyl derivative of beta cyclodextrin, a number of other cyclodextrin derivatives are known. See, for example, U.S. Pat. Nos. 5,376,645 (Stella et al.) and 4,870,060 (Muller).
Typically, multi-dose pharmaceutical products contain preservatives in order to maintain sterility after opening and during use. Antimicrobial preservation of cyclodextrin-containing formulations can present special problems. For example, Loftsson et al., Drug Development and Industrial Pharmacy, 18 (13), 1477-1484 (1992), have investigated interactions between several commonly used preservatives and 2-hydroxypropyl-.beta.-cyclodextrin (HP.beta.CD). Loftsson et al. report that the interactions were twofold: (i) the preservative molecule can displace a drug molecule from the cyclodextrin cavity, thus reducing the solubilizing effects of the cyclodextrin; and (ii) the antimicrobial activity of the preservative can be reduced by the formation of preservative-cyclodextrin inclusion complexes. Specifically, Loftsson et al. report that chlorobutanol, methylparaben and propylparaben have little or no preservative activity in the tested HP.beta.CD solutions. Additionally, Loftsson et al. found that benzalkonium chloride (with the possible exception of the micro-organism, Ps. aeruginosa) and chlorhexidine gluconate did possess significant preservative activity. In contrast, Simpson, FEMS Microbiology Letters, 90, 197-200 (1992), reports that cyclodextrins can inactivate the antimicrobial activity of certain quaternary ammonium compounds. See also, Miyajima et al., Chem. Pharm. Bull., 35(1), 389-393 (1987), regarding the interaction of short-chain alkylammonium salts with cyclodextrins in aqueous solutions, which concluded that .alpha.-, .beta.-, and .gamma.-cyclodextrins form complexes with alkylammonium salts having alkyl groups longer than n-butyl, n-hexyl, and n-decyl, respectively.
Benzalkonium chloride (BAC) is the most popular preservative for ophthalmic drug preparations. BAC, as defined in United States Pharmacopeia XIX, is an alkylbenzyldimethyl-ammonium chloride mixture with alkyl chains or homologs beginning with n-C.sub.8 H.sub.17 and extending through higher homologs of C.sub.10 -, C.sub.12 -, C.sub.14 -, and C.sub.16 -alkyl chains. In our attempts to preserve pharmaceutical formulations containing a cyclodextrin with BAC, however, we have found that cyclodextrin-preservative interactions can significantly reduce or inactivate the preservative efficacy of BAC, when BAC is employed at non-toxic levels.
EP 0 119 737 A2 (Takeda Chem. Ind., Ltd.) discloses aqueous pharmaceutical compositions comprising an active ingredient, a cyclodextrin and a phenol derivative as a preservative. The phenol derivative has the formula ##STR2## where R is alkyl, X is halogen, n is an integer of 0 to 2, and m is an integer of 1 to 3. According to this reference, formulations containing a cyclodextrin and a paraben preservative (methyl-, ethyl-, propyl-, and butylparaben) suffered a significant decrease in the antimicrobial activity of the preservative, while formulations containing a cyclodextrin and a phenol derivative of the formula above did not.
JP 60149530 A (Takeda Chem. Ind., Ltd.) discloses aqueous compositions of a principal agent and a cyclodextrin where the compositions contain as a preservative a chlorhexidine derivative of the formula ##STR3## where A is [independently] (un)substituted phenyl; n is 3-9; and the polymethylene chain may be interrupted by an oxygen atom or an aromatic ring.
JP 01016728 A (Santen Seiyaku KK) discloses antiseptic aqueous preparations containing a drug, a cyclodextrin and a cationic surfactant as a preservative. By adding a cyclodextrin or cyclodextrin derivative, cationic surfactants commonly incompatible with certain drugs can be combined. Disclosed cationic surfactants are benzalkonium chloride, benzethonium chloride or chlorohexidine gluconate. Disclosed drugs include sodium hyaluronate, pilocarpine hydrochloride, lysosyme chloride, Na.sub.2 chondroitin sulfate, glycyrrhetinate, pirenoxine, sodium chromoglycate, and dimethylisopropylazulene sodium sulfate.
JP 6016547 A (Wakamoto Pharm. Co. Ltd.) discloses eye drop compositions containing diclofenac sodium and a water soluble cyclodextrin compound. The reference also discloses that these compositions can be preserved using benzalkonium chloride, benzethonium chloride and chlorhexidine gluconate as cationic surfactants; methylparaben, ethylparaben, propylparaben and butylparaben as parabens; and phenylethyl alcohol and benzyl alcohol as alcohols.
Even if their antimicrobial preservative efficacy is not significantly reduced by interactions with cyclodextrins, benzyl or phenylethyl alcohol and paraben preservatives may present cytotoxicity, evaporation loss, comfort and/or stability problems. Other compounds or systems capable of effectively preserving pharmaceutical formulations containing cyclodextrins are desirable.